To evaluate the role of Coxsackie B viruses in the pathogenesis of insulin-dependent (juvenile-onset, type 1) diabetes mellitus (IDDM), attempts were made to correlate virus-specific IgM responses with HLA genes, autoimmune responses, and C-peptide secretion. HLA DR3, DR4, or both were present in 73 of 90 (81%) diabetic patients; 22 of 23 (96%) with Coxsackie-B-virus-specific IgM had at least one of these HLA types, compared with 51 of 67 (76%) without virus-specific IgM. There was no correlation between HLA A, B, or C types or immunoglobulin allotypes and virus-specific IgM responses. 16 of 22 (64%) patients with Coxsackie-B-virus-specific IgM compared with 26 of 72 (36%) without had complement-fixing islet-cell antibodies; no relation was found between virus-specific IgM and antibodies against thyroid or adrenal tissue or parietal cells. C-peptide secretion was significantly lower in patients with Coxsackie-B-virus-specific IgM.